During sensitization (IgE), desensitization of IgE/MC reactivity to the hapten-carrier complex develops
A cornerstone of the new interpretation of (drug) allergy is the hypothesis that the sensitization of MC by a gradual increase of specific IgE in the presence of antigen reduces MC reactivity to the specific antigen (1) (table 2, figure 2). The underlying mechanism of this antigen-specific unresponsiveness is not clear. It could be similar or identical to the process of drug desensitization: Inin-vitro models it has been shown that this antigen-specific process blocks calcium flux, impacts the antigen/IgE/FcεRI complex-internalization and prevents the acute and the late-phase reactions as well as mast cell mediator release (20). Importantly, this unresponsiveness of MCs is specific for the antigen-IgE complex, while MC-reactivity to other antigens by IgE cross-linking persists. The MC unresponsiveness just covers the antigen concentration used for inducing unresponsiveness, normally determined by the serum concentration of the drug. When the MCs that carry specific IgEs are confronted with a suddenly higher concentration of specific antigen than the tolerizing dose, the unresponsiveness of MCs is broken and the MCs react/degranulate. This phenomenon is known as “breakthrough reaction” in drug desensitizations. It occurs, when the last increase of the drug concentration was too large (21). When no antigen exposure occurs, this MC-unresponsiveness is decreasing over time and an allergic reaction may re-appear to previously tolerated antigen concentrations: MC-unresponsiveness can be re-adjusted by a natural exposure: e.g. the first bee stings in spring in already sensitized beekeepers may cause urticaria, but these generalized reactions to stings disappear in the following weeks (table 2) (22) and may also disappear by intended antigen-exposure (“immunotherapy”) (22,23).
Importantly, this MC-unresponsiveness may represent the normalresponse when IgE is formed to protein antigens (allergens) and the antigen is still present (table 2). It is different from the long-lasting T cell-based tolerance mechanism (24), as it is based on the unresponsiveness of MCs and probably also basophils, both carrying IgE-FcεRI. The concept of MC-unresponsiveness also implies that at least one scope of allergen-specific IgE is to react via MC to alocally relatively high allergen concentration, but not to normal, systemically available levels of allergen.
MC-unresponsiveness could also explain the high number of sensitized but not allergic individuals in various studies on the prevalence of allergic diseases (25). Sensitization is often identified by positive skin tests (prick, i.d.), where locally an excess amount of allergen is applied (26). The concentrations used for skin tests break MC-unresponsiveness and results in a local wheal and flare reaction. Since epidemiological studies revealed that about half of the skin test-positive individuals do not show symptoms to pollens (seasonal rhino-conjunctivitis), they may be unresponsive to the usual concentrations of pollen allergens reaching the tissue (26, 27). However, they react to the high local allergen concentrations applied in skin tests. This suggests that the difference between allergic (sensitized and symptomatic) and sensitized (but asymptomatic) individuals is that the amount of allergen reaching the tissue is higher in allergic individuals. More likely seems that in allergic individuals the IgE coated MC react to lower local concentrations of allergen; IgE mediated allergy is thus a) defined by the formation of antigen-specific IgE, and b) the MC-(un)responsiveness to the antigen/allergen reaching the tissue is not well adjusted.